The overall goal of this proposal is to develop effective chemopreventive strategies and understand the molecular mechanism of colon tumor inhibition by a combination of statins (3- hydroxy-3methyl glutaryl CoA reductase (HMG-R) inhibitors) and polyamine inhibitor, DFMO against colon cancer. Colorectal cancer is one of the most common malignancies in both men and women in the US. In developing translational strategies, a preferable approach is to target multiple signaling pathways that selectively contribute towards tumor growth, so that it provides a synergistic/additive efficacy. Colon tumor cells produce high levels of polyamines endogenously through the activation of ornithine decarboxylase (ODC). DFMO selectively inhibits ODC activity and thereby endogenous polyamine synthesis and colon tumor growth. New insights into the transport of polyamines in tumor cells by caveolin-1 (cav-1) and SLC3A2 mediated pathways suggest that new approaches are needed for effective polyamine regulation in tumor cells. In spite of the fact that DFMO inhibits endogenous polyamine synthesis, tumor cells can still uptake extracellular polyamines through a cav-1 dependent endocytic mechanism. Further, Cav-1 plays an important role in the generation of nitric oxide (NO) and activation of AKT and Rho-signaling, leading to enhanced tumor cell proliferation and invasion. Our preliminary results suggest, that a combination of rosuvastatin with low-dose DFMO suppresses azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF), and aberrant crypt cell proliferation. Our in vitro and in vivo results suggest that cav-1 plays an important role in colon cancer, and statins exhibit colon tumor inhibition in part by modulating cav-1. Therefore, we want to develop a combination of statin and DFMO for colon cancer prevention/treatment and understand the role of cav-1 in colon cancer and its possible regulation by miRNAs.
Specific aims are 1) Determine the in vivo efficacy of Rosuvastatin (Crestor) in a F344 rat colon carcinogenesis model (maximum tolerated/optimal dose selection;dose- response effects;and effectiveness during promotion/progression stages (early/late interventions). 2) Determine the combinational efficacy of atorvastatin/rosuvastatin and DFMO on the progression of colonic ACF (post-initiation/early stage) or adenoma (progression/late stage) to colon adenocarcinoma formation in rats. We also want to determine the effect of statins and DFMO on the levels of cav-1, polyamines, ODC activity, NO (iNOS and eNOS activities), SLC3A2, AKT and Rho signaling proteins, miRNA modifications in colonic mucosa and tumor tissues and correlate these results with colon tumor inhibition. 3) Define the role of cav-1 in colon carcinogenesis using cav-1-/- knockout mouse model and determine the effect of statins with or without DFMO on carcinogen induced colon tumor formation in cav- 1-/- and cav-1+/+ mice. In addition, proposed research will elucidate the role of selective miRNAs on the regulation of cav-1 in colon cancer cells, and assess the possible modulatory role of statins and DFMO on cav-1 miRNA regulation.

Public Health Relevance

Colorectal cancer is one of the most common malignancies in both men and women in the US accounting for 50,000 deaths annually. Developing translational strategies to prevent the malignant progression of colon tumor growth is an ideal approach. The proposed studies will produce a detailed preclinical evaluation, thus setting the stage for the eventual clinical assessment of statins either alone or in combination with low-dose ODC inhibitor for colon cancer prevention and treatment. In addition, these studies will also provide valuable information on the most widely used statin, rosuvastatin which exerts multiple health benefits in humans and especially for colon cancer prevention, when it is specifically administered during the adenoma stage of colon carcinogenesis. Furthermore, the proposed studies will provide mechanistic insight into how a combination of statins and ODC inhibitors provides enhanced suppression of cellular polyamine levels leading to synergistic colon tumor growth inhibition and finally elucidate the role of cav-1 in colon cancer/prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA094962-10
Application #
8454510
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Malone, Winfred F
Project Start
2002-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$271,796
Indirect Cost
$88,150
Name
University of Oklahoma Health Sciences Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
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Rao, Chinthalapally V; Sanghera, Saira; Zhang, Yuting et al. (2016) Systemic Chromosome Instability Resulted in Colonic Transcriptomic Changes in Metabolic, Proliferation, and Stem Cell Regulators in Sgo1-/+ Mice. Cancer Res 76:630-42
Madka, Venkateshwar; Mohammed, Altaf; Li, Qian et al. (2016) Targeting mTOR and p53 Signaling Inhibits Muscle Invasive Bladder Cancer In Vivo. Cancer Prev Res (Phila) 9:53-62
Janakiram, Naveena B; Mohammed, Altaf; Bryant, Taylor et al. (2016) Potentiating NK cell activity by combination of Rosuvastatin and Difluoromethylornithine for effective chemopreventive efficacy against Colon Cancer. Sci Rep 6:37046
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Pathuri, Gopal; Li, Qian; Mohammed, Altaf et al. (2014) Synthesis and in vivo evaluation of N-ethylamino-2-oxo-1,2-dihydro-quinoline-3-carboxamide for inhibition of intestinal tumorigenesis in APC(Min/+) mice. Bioorg Med Chem Lett 24:1380-2
Mohammed, Altaf; Janakiram, Naveena B; Madka, Venkateshwar et al. (2014) Eflornithine (DFMO) prevents progression of pancreatic cancer by modulating ornithine decarboxylase signaling. Cancer Prev Res (Phila) 7:1198-209
Janakiram, Naveena B; Mohammed, Altaf; Zhang, Yuting et al. (2013) Chemopreventive efficacy of raloxifene, bexarotene, and their combination on the progression of chemically induced colon adenomas to adenocarcinomas in rats. Cancer Prev Res (Phila) 6:1251-61

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